JP2006526590A - Matrix metalloproteinase inhibitor - Google Patents

Abstract

Compounds of formula (I): wherein: Q represents an optionally substituted 5- or 6-membered aryl or heteroaryl ring; X represents O, S, NR<SUP>5 </SUP>or CR<SUP>6 </SUP>R<SUP>7</SUP>; Y represents CHOH, CHSH, NOR<SUP>8</SUP>, CNR<SUP>8 </SUP>or CNOR<SUP>8</SUP>; Z represents a bond, CR<SUP>10</SUP>R<SUP>11</SUP>, O, S, SO, SO<SUB>2</SUB>, NR<SUP>10</SUP>, OCR<SUP>10</SUP>R<SUP>11</SUP>, CR<SUP>10</SUP>R<SUP>11 </SUP>O or Z, R<SUP>4 </SUP>and Q together form an optionally substituted fused tricyclic group; R<SUP>1</SUP>, R<SUP>1'</SUP>, R<SUP>3 </SUP>and R<SUP>3'</SUP> each independently represents H, C<SUB>1-6 </SUB>alkyl or C<SUB>1-4 </SUB>alkylaryl; R<SUP>2 </SUP>represents CO<SUB>2</SUB>R<SUP>8</SUP>, CONR<SUP>5</SUP>OR<SUP>9 </SUP>or NR<SUP>5</SUP>COR<SUP>9</SUP>; R<SUP>4 </SUP>represents optionally substituted 5- or 6-membered aryl or heteroaryl; R<SUP>5 </SUP>represents H or C<SUB>1-3 </SUB>alkyl; R<SUP>6 </SUP>and R<SUP>7 </SUP>each independently represents H, C<SUB>1-3 </SUB>alkyl or halo; R<SUP>8 </SUP>represents H or C<SUB>1-2 </SUB>alkyl; R<SUP>9 </SUP>represents H or C<SUB>1-3 </SUB>alkyl; R<SUP>10 </SUP>and R<SUP>11 </SUP>each independently represents H, C<SUB>1-6 </SUB>alkyl or C<SUB>1-4 </SUB>alkylaryl; and physiologically functional derivatives thereof, processes for their preparation, pharmaceutical formulations containing them and their use as inhibitors of matrix metalloproteinase enzymes (MMPs) are described.

Description

  The present invention relates to novel chemical compounds, methods for their preparation, pharmaceutical formulations containing them, and their use in therapy.

  The compounds of the present invention are inhibitors of matrix metalloproteinase enzyme (MMP).

  Matrix metalloproteinase enzymes play an important role in the degradation and remodeling of extracellular matrix components. Examples of MMPs include collagenase 1, 2 and 3, gelatinase A and B, stromelysin 1, 2 and 3, matrilysin, macrophage metalloelastase, enamelin, and membrane-type 1MMP, 2MMP, 3MMP and 4MMP. These enzymes are secreted by connective tissue cells and inflammatory cells. Enzyme activation not only causes tissue damage, but also induces increased infiltration of inflammatory cells into the tissue, resulting in further production of the enzyme and subsequent tissue damage. For example, elastin fragments produced by MMP degradation are believed to stimulate inflammation by attracting macrophages to the site of MMP activity. Thus, inhibiting MMP provides a means for treating disease states in which inappropriate metalloprotease activity causes connective tissue degradation and inflammation.

In one aspect, the invention provides a compound of formula (I):

(Where
Q represents an optionally substituted 5- or 6-membered aryl or heteroaryl ring;
X represents O, S, NR ⁵ , or CR ⁶ R ⁷ ;
Y represents CHOH, CHSH, NOR ⁸ , CNR ⁸ , or CNOR ⁸ ;
Z represents a bond, CR ¹⁰ R ¹¹ , O, S, SO, SO ₂ , NR ¹⁰ , OCR ¹⁰ R ¹¹ , CR ¹⁰ R ¹¹ O, or Z, R ⁴ and Q are taken together Forming an optionally substituted fused tricyclic group;
R ¹ , R ¹ ′, R ³ and R ³ ′ independently of one another represent H, C _1-6 alkyl, or C _1-4 alkylaryl;
R ² represents CO ₂ R ⁸ , CONR ⁵ OR ⁹ , or NR ⁵ COR ⁹ ;
R ⁴ represents optionally substituted 5 or 6 membered aryl or heteroaryl;
R ⁵ represents H or C _1-3 alkyl;
R ⁶ and R ⁷ independently of one another represent H, C _1-3 alkyl, or halogen;
R ⁸ represents H or C _1-2 alkyl;
R ⁹ represents H or C _1-3 alkyl;
R ¹⁰ and R ¹¹ independently of one another represent H, C _1-6 alkyl, or C _1-4 alkylaryl)
And the physiologically functional derivatives thereof (excluding 6H-dibenzo [b, d] pyran-3-pentanoic acid (1-dihydroxy-6,6,9-trimethyl) except that As a condition:
Q represents phenyl; X is O, S or CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ independently of one another represent H or C _1-3 alkyl; Z is a bond, C _{2-4 represents} alkylene, S, SO, SO ₂ , OCH ₂ , or CH ₂ O; when Y represents CHOH, R ⁴ represents a substituent X′W ′ (wherein X ′ represents —NR ¹ C (O) NR ^2- , -NR ¹ C (O)-, -NR ¹ C (O) O-, -C (O) NR ^2- , or -OC (O) NR ^2- (where R ¹ and R ² are independently selected from hydrogen, C _1-4 alkyl and C _1-4 haloalkyl) and W ′ is hydrogen, or hydrogen, C _1-4 alkyl, C _{1- A} C _1-12 hydrocarbyl group optionally substituted by one or more groups independently selected from ₄ alkoxy, hydroxy, C _1-4 haloalkyl, and C _1-4 haloalkoxy) Not phenyl substituted at the ortho position by; and
R ⁴ , Z and Q together are a group:

(Where
R ¹ ′ is H, C _1-6 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _1-6 alkanoyl, C _1-4 alkanoyl C _1-4 alkyl, aryl, aryl C _1-4 alkyl, Aryl-C _1-4 alkoxy C _1-4 alkyl, aryl C _1-4 alkanoyl, arylcarbonyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _1-4 alkoxy C _1-4 alkyl, heteroaryl C _1-4 alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclyl C _1-4 alkyl, heterocyclyl C _1-4 alkoxy C _1-4 alkyl, heterocyclyl C _1-4 alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclyl C _1-4 alkyl, carbocyclyl C _1-4 alkoxy C _1-4 alkyl, carbocyclyl C _1-4 alkanoyl, carbocyclylalkyl carbonyl, C _1-4 alkylsulfonyl, N, N-di -C _1-4 A A kill aminosulfonyl or NC _1-4 alkylaminosulfonyl, wherein, R ¹ 'is (optionally substituted by 3 or fewer fluro (Fluro) substituents) C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoyl, carboxy, hydroxy, halogen, cyano, amino, NC _1-4 alkylamino, N, N-di-C _1-4 alkylamino, C _1-4 alkanoylamino, mercapto , C _1-4 alkylsulfonyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfanyl, nitro, heteroaryl C _1-4 alkanoylamino, or C _1-4 3 or less independently selected from alkoxycarbonyl Optionally substituted by a substituent of
R ² ′ is hydrogen, C _1-4 alkyl (optionally substituted by hydroxy), C _1-4 alkoxy, cyano, nitro, halogen, amino, NC _1-4 alkylamino, or N, N Selected from -dialkylamino;
R ⁴ ′ is selected from hydrogen, C _1-4 alkyl, halogen, or nitro)
If you form
X is NH or CR ⁶ R ⁷ ;
Y is CHOH;
R ² is not CO ₂ R ^{8 where} R ⁸ is C _1-2 alkyl)
I will provide a.

References to “aryl” include monocyclic carbocyclic aromatic rings (eg, phenyl) and bicyclic carbocyclic aromatic rings (eg, naphthyl), and references to “heteroaryl” include nitrogen Monocyclic and bicyclic heteroaromatic rings containing 1 to 3 heteroatoms selected from oxygen and sulfur. Examples of monocyclic heteroaromatic rings include, for example, pyridinyl, pyrimidinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl, and bicyclic heteroaromatic rings Examples of are, for example, benzimidazolyl, quinolinyl, or indolyl. Carbocyclic aromatic rings and heterocyclic aromatic rings are, for example, one or more C _1-6 alkyl, C _2-6 alkenyl, halogen, (CH ₂ ) _0-4 OR ⁶ , (CH ₂ ) _0-4 SR ⁶ , SO ₂ R ⁶ , COR ⁶ , aryloxy, thioaryl, cyano, hydroxy, nitro, NR ⁶ R ⁷ , -NR ⁶ COR ⁷ , -OCF ₃ , -CF ₃ , COOR ⁷ , -OCHCF ₂ , optionally substituted with groups such as —SCF ₃ , —CONR ⁶ R ⁷ , —SO ₂ NR ⁶ R ⁷ .

  Reference to alkyl includes both linear and branched aliphatic isomers of the corresponding alkyl. It will be understood that the description of alkylene and alkoxy should be judged similarly.

Preferably R ¹ and R ¹ ′ represent hydrogen with respect to each other.

Preferably R ² represents CO ₂ R ⁸ , more preferably CO ₂ H.

Preferably R ³ and R ³ ′ represent hydrogen with respect to each other.

Preferably R ⁴ represents optionally substituted phenyl or heteroaryl.

Preferably, X represents CH _2.

  Preferably Y represents CHOH.

Preferably Z represents a bond or Z, R ⁴ and Q together represent a fused tricyclic group.

A preferred subgroup of compounds represented by formula (I) is of formula (Ia):

(Where:
T is absent or represents O, S, NR ¹⁷ or CR ¹⁷ R ¹⁸ ;
--- represents any bond;
R ¹⁵ and R ¹⁶ are independently of each other halogen, cyano, nitro, OR ¹⁷ , SR ¹⁷ , COR ¹⁷ , NR ¹⁸ COR ¹⁷ , CONR ¹⁷ R ¹⁸ , optionally substituted phenoxy, or OR ¹⁷ Represents optionally substituted C _1-6 alkyl;
R ¹⁷ represents H, C _1-6 alkyl or C _1-4 alkylaryl;
R ¹⁸ represents H or C _1-6 alkyl;
m and n independently of one another represent 0 or an integer of 1, 2 or 3;
(However, if T is not present, R ¹⁵ is not ortho-position NR ¹⁸ COR ¹⁷ or CONR ¹⁷ R ¹⁸ )
As well as its physiologically functional derivatives.

  Preferably n is 0 and m is 1.

Preferably, R ¹⁵ represents a para substituent selected from NO ₂ , C _1-6 alkyl, C _1-6 alkoxy, halogen, SC _1-6 alkyl, CN, or COC _1-6 alkyl.

  The term “physiologically functional derivative” includes, for example, a compound of formula (I) that has a physiological function similar to that of the free compound of formula (I) by being convertible into formula (I) in vivo. Any of the compounds of formula (I), which can directly or indirectly provide a compound of formula (I) or an active metabolite or residue thereof when administered to a user Pharmaceutically acceptable esters, amides and carbamates, salts and solvates.

  Suitable salts of the compound of formula (I) include physiologically acceptable salts, and may be physiologically acceptable but useful for the preparation of compounds of formula (I) and physiologically acceptable salts thereof. Possible salts are mentioned. If appropriate, the acid addition salts are inorganic or organic acids such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, benzoate, citrate, succinate, lactate. , Tartrate, fumarate, maleate, 1-hydroxy-2-naphthoate, palmoate, methanesulfonate, formate or trifluoroacetate.

  Examples of solvates include hydrates.

  Where a compound of formula (I) contains a chiral center, the present invention encompasses mixtures of enantiomers (including racemic mixtures) and diastereoisomers as well as individual enantiomers. In general, the compound of formula (I) is preferably used in the form of a purified single enantiomer.

  Compounds of formula (I) and salts and solvates thereof can be prepared by the methods described below, which constitutes a further aspect of the invention.

The first method (A) according to the invention aimed at preparing a compound of formula (I) (wherein Z represents a bond) is a compound of formula (II):

(Wherein R ¹ , R ¹ ′, R ² , R ³ , R ³ ′, Q, X, and Y are as previously defined for formula (I) and L represents a leaving group) A reagent suitable for introducing the group R ⁴ Z (for example the compound R ⁴ ZB (OH) ₂ ), preferably a catalyst (such as a noble metal catalyst such as palladium) and a suitable base ( Reacting in the presence of an alkali metal carbonate or the like (eg, cesium carbonate). This reaction is conveniently carried out in a suitable solvent such as a polar organic solvent (eg dimethylformamide). Suitable leaving groups represented by L include halides, particularly bromide or iodide.

An alternative method (B) aimed at preparing compounds of formula (I) (wherein Y represents NOH) is of formula (III):

(Wherein R ⁴ , Z, Q, X, R ¹ , R ¹ ′, R ³ , R ³ ′, and R ² are as previously defined for formula (I)).
Oxidation of the compound represented by: Suitable oxidizing agents include meta-chloroperbenzoic acid or t-butyl hydroperoxide in a suitable solvent (such as dichloromethane or toluene). This reaction is preferably performed at room temperature (eg, about 18-25 ° C.).

Alternatively, another method (C) aimed at preparing a compound of formula (I) (wherein X represents O or S and Y represents CHOH) may be prepared in the presence of a base (IV ):

Wherein R ⁴ , Z and Q are as previously defined for formula (I) and X represents O or S
A compound represented by formula (VA) or (VB):

(Wherein R ¹ , R ¹ ′, R ³ , R ³ ′, and R ² are as previously defined for formula (I) and L is a leaving group)
Reaction with a compound represented by the formula, and if necessary, subsequent reduction. Suitable bases include alkali metal alkoxides (such as potassium t-butoxide) dissolved in a suitable solvent (such as dimethylformamide) at a temperature of about 15-50 ° C. Suitable leaving groups represented by L include halides, particularly bromide and iodide. Suitable reducing agents will be readily apparent to those skilled in the art and include, for example, sodium borohydride.

  It is also appreciated that a compound of formula (I) can be prepared from another compound of formula (I) by interconversion using standard methods in the field of synthetic chemistry (oxidation, reduction, substitution, deprotection, etc.). It will be clear to the contractor.

The compound represented by the formula (II) (wherein X is CR ⁶ R ⁷ (wherein R ⁶ and R ⁷ each independently represents H or C _1-3 alkyl)) In the presence of a suitable base, formula (VI):

Wherein L and Q are as defined for formula (II) and X is CR ⁶ R ^{7 wherein} R ⁶ and R ⁷ are each independently H or C _1-3 alkyl L ² represents a leaving group having a higher substitution activity than L)
A compound represented by the formula (X):

(Wherein R ¹ , R ¹ ′, R ² , R ³ and R ³ ′ are as previously defined for formula (I))
It can prepare by making it react with the compound represented by these. Suitable bases include alkali metal hydrides (such as sodium hydride) and alkyl lithium (such as n-butyllithium). This reaction is preferably performed in an anhydrous organic solvent (such as tetrahydrofuran) at a low temperature (eg, about 0 ° C.). Other compounds of formula (II) are commercially available or can be obtained from commercially available compounds by methods well known to those skilled in the art.

The compound of formula (III) is prepared by reacting the compound of formula (VII):

(Wherein R ⁴ , Z, Q, X, R ¹ and R ¹ ′ are as previously defined for formula (I))
A compound represented by formula (VIII):

(Wherein R ² , R ³ and R ³ ′ are as previously defined for formula (I))
It can prepare by making it react with the compound represented by these.

  The compounds of the formulas (IV), (VII) and (IX) are known or known methods, such as N Miyaura and A Suzuki (Chem. Rev., 1995, 95, 2457-2483) and It can be prepared by the method reported by A. Suzuki (J. Oranometallic Chem., 1999, 576, 147-168).

  Compounds of formula (VA), (VB), (VIII) and (X) are known or can be prepared from known compounds by methods well known to those skilled in the art. For example, the epoxide of formula (VA) can be prepared from the corresponding alkene, for example by oxidation with metachloroperbenzoic acid.

  The enantiomeric compounds of the present invention can be obtained by (a) separation of the components of the corresponding racemic mixture, for example by chiral chromatography, enzymatic resolution methods, or by preparation and separation of suitable diastereoisomers (b) Can be obtained by direct synthesis from a suitable chiral starting material, or by a method similar to the method described above using (c) a chiral reagent.

  Optional conversion of the compound of formula (I) to the corresponding salt can preferably be carried out by reaction with a suitable acid or base. Any conversion of the compound of formula (I) to the corresponding solvate or other physiologically functional derivative can be carried out by methods known to those skilled in the art.

  The compounds of formula (I) may be useful in the treatment of all conditions where inhibition of matrix metalloproteinases is effective, particularly in the treatment of inflammatory diseases and autoimmune disorders.

  Examples of inflammatory conditions and autoimmune disorders in which the compounds of the present invention may have medicinal effects include respiratory diseases such as asthma (including allergen-induced asthmatic reactions), cystic fibrosis, bronchitis (chronic bronchitis) Chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), chronic transpulmonary inflammation, rhinitis and upper respiratory inflammatory disorder (URID), ventilator-induced lung injury, silicosis, pulmonary sarcoidosis, Idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, arthritis, e.g. rheumatoid arthritis, osteoarthritis, infectious arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, Reiter syndrome, gouty arthritis and prosthetic joint dysfunction, Gout, acute synovitis, spondylitis and non-arthritic symptoms such as disc herniation / damaged disc / prolapse disc syndrome, myxitis, tendonitis, tendon synovitis, connective tissue syndrome and ligament sprain And other inflammatory symptoms associated with localized musculoskeletal damage, inflammatory diseases of the gastrointestinal tract, eg ulcerative colitis, diverticulitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome and gastritis, multiple sclerosis Disease, systemic lupus erythematosus, scleroderma, autoimmune exocrine adenopathy, autoimmune encephalomyelitis, diabetes, tumor angiogenesis and metastasis, breast cancer, colon cancer, rectal cancer, lung cancer, renal cancer, ovarian cancer, Gastric cancer, uterine cancer, pancreatic cancer, liver cancer, oral cancer, cancer including throat cancer and prostate cancer, melanoma, acute leukemia and chronic leukemia, alveolar pyorrhea, neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, epilepsy, Muscle degeneration, inguinal hernia, retinal degeneration, diabetic retinopathy, macular degeneration, ocular inflammation, bone resorption disease, osteoporosis, marble bone disease, graft-to-host reaction, allograft rejection, sepsis, endotoxemia , Toxic shock Group, tuberculosis, conventional interstitial organizing pneumonia and idiopathic organizing pneumonia, bacterial meningitis, systemic cachexia, secondary cachexia of infection or malignant tumor, acquired immune deficiency syndrome (AIDS) secondary cachexia Quality, malaria, leprosy, cutaneous leishmaniasis, Lyme disease, glomerulonephritis, glomerulosclerosis, renal fibrosis, liver fibrosis, pancreatitis, hepatitis, endometriosis, pain, eg inflammation and / or trauma Pain associated with, inflammatory diseases of the skin, such as dermatitis, skin diseases, skin ulcers, psoriasis, eczema, systemic vasculitis, vascular dementia, thrombosis, atherosclerosis, restenosis, reperfusion Injury, plaque calcification, myocarditis, aneurysm, stroke, pulmonary hypertension, left ventricular remodeling, and heart failure.

  Important major diseases include COPD and respiratory inflammatory diseases, as well as joint and vascular diseases.

  It will be apparent to those skilled in the art that the description herein regarding treatment extends to the prevention and treatment of certain diseases.

  Accordingly, as a further aspect of the invention, there is provided a compound of formula (I) or a physiologically acceptable derivative thereof for use in medicine.

  According to another aspect of the invention, there is provided the use of a compound of formula (I) or a physiologically acceptable derivative thereof in the manufacture of a medicament for the treatment of inflammatory conditions or autoimmune disorders.

  In a further or alternative embodiment, a method of treating a human or animal subject suffering from or susceptible to an autoimmune disease or inflammatory disease, wherein the human or animal subject Wherein said method comprises administering a compound of formula (I) or a physiologically functional derivative thereof.

  The compounds according to the invention can be formulated for administration in any convenient way. Accordingly, the present invention also includes within its scope a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable derivative thereof, if desired, together with one or more physiologically acceptable diluents or carriers. Include.

  Furthermore, there is also provided a method for preparing such a pharmaceutical formulation comprising mixing the ingredients.

  The compounds according to the invention can be formulated, for example, for oral administration, inhalation administration, intranasal administration, topical administration, buccal administration, parenteral administration or rectal administration, preferably for oral administration.

  Tablets and capsules for oral administration are conventional additives such as binders such as syrup, gum arabic, gelatin, sorbitol, tragacanth gum, starch mucus, cellulose, or polyvinylpyrrolidone; fillers such as lactose, microcrystalline Cellulose, sugar, corn starch, calcium phosphate, or sorbitol; lubricants such as magnesium stearate, stearic acid, talc, polyethylene glycol, or silica; disintegrants such as potato starch, croscarmellose sodium, or starch glycolic acid Sodium; or may include a wetting agent such as sodium lauryl sulfate. The tablets can be coated by methods well known in the art. Oral liquid formulations may be, for example, in the form of an aqueous or oily suspension, solution, emulsion, syrup, or elixir. Alternatively, it can be provided as a dry product for construction with water or other suitable vehicle prior to use. Such liquid formulations include conventional additives such as suspending agents such as sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats; Lecithin, sorbitan monooleate, or gum arabic; non-aqueous vehicles (which may include edible oils) such as almond oil, refined coconut oil, oily esters, propylene glycol, or ethyl alcohol; or preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid may be included. These preparations may also contain buffer salts, flavoring agents, coloring agents and / or sweetening agents (eg mannitol), if desired.

  The compounds according to the invention for topical administration can be formulated as creams, gels, ointments or lotions, or as a transdermal patch. Such compositions can be prepared, for example, by adding suitable thickening agents, gelling agents, emulsifying agents, stabilizing agents, dispersing agents, suspending agents and / or colorants to form an aqueous base or oil base. They can be formulated together.

  Lotions can be formulated with an aqueous or oily base, but generally one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents Agents can also be included. Further, the lotion may contain a preservative.

  For buccal administration, the composition may be in the form of tablets or lozenges formulated in conventional manner.

  The present compounds can also be formulated as suppositories containing a conventional suppository base such as cocoa butter or other glycerides.

  The compounds according to the invention can also be formulated for parenteral administration by bolus injection or continuous infusion, eg in unit dosage forms as ampoules, vials, small infusions or pre-filled syringes or with additional preservatives Multiple dose containers can be provided. The composition may be in the form of a solution, suspension or emulsion dissolved in an aqueous or non-aqueous vehicle, and a formulation agent such as an antioxidant, buffer, antibacterial agent, and / or isotonic agent. (formulatory agent) may be contained. Alternatively, the active ingredient may be in powder form intended to be configured using a suitable vehicle (eg, sterilized pyrogen-free water) prior to use. This dry solid form can be prepared by aseptically filling sterilized powders into individual sterilized containers, or by aseptically filling each container with sterilized liquid and freeze-drying.

  The pharmaceutical composition according to the present invention also contains other therapeutic agents such as anti-inflammatory agents (such as corticosteroids (e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furanate, triamcinolone acetonide or budesonide)) or NSAIDs (e.g. sodium cromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotriene antagonists, CCR-3 antagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) Or in combination with beta-adrenergic drugs (eg salmeterol, salbutamol, formoterol, fenoterol or terbutaline and their salts), or anti-infectives (eg antibiotics, antiviral drugs) be able to.

  It will be appreciated that when a compound of the invention is administered in combination with other therapeutic agents normally administered by inhalation or nasal route, the resulting pharmaceutical composition can be administered by inhalation or nasal route.

  The compounds of the present invention are conveniently administered in an amount of, for example, 0.01-100 mg / kg body weight, preferably 0.1-25 mg / kg body weight, more preferably 0.3-5 mg / kg body weight. The compound can be administered more than once a day to equal the total daily dose. The exact dose will of course depend on the age and condition of the patient and the particular route of administration chosen, but will ultimately be at the discretion of the attending physician.

  When the compounds according to the invention are administered within the above-mentioned dose ranges, there appears to be no toxic effects.

  The compounds of the invention can be tested for in vitro activity according to the following assay.

The fluorescent peptide substrate used in the MMP-12 assay is FAM-Gly-Pro-Leu-Gly-Leu-Phe-Ala-Arg-Lys (TAMRA). In the formula, FAM represents carboxyfluorescein, and TAMRA represents tetramethylrhodamine. MMP12 catalytic domain (residues 106-268) protein was expressed in the form of insoluble inclusion bodies in E. coli and stored in a concentrated solution under denaturing conditions (8M guanidine hydrochloride). The enzyme was refolded to the active form in situ by direct dilution after initiation of the assay reaction. 51 μL of the reaction was added to a NUNC ™ black and square 384-well plate (each well dissolved in 50 mM HEPES, pH 7.5, 150 mM NaCl, 10 mM CaCl ₂ , 1 μM ZnAc, 0.6 mM CHAPS, and 2% DMSO) Substrate, 20 nM enzyme and 0.001-100 μM inhibitor). Positive control wells do not contain inhibitors. Negative control wells are pre-performed with EDTA quenching (see below) or by removing the enzyme. Incubate the reaction for 120 minutes at room temperature and then quench by adding 15 μL of 100 mM EDTA. Product formation in each well is quantified by measuring fluorescence using a Molecular Devices Acquest. The excitation wavelength is set at 485 nM and the emission wavelength is 530 nM. IC ₅₀ values are first calculated as percent inhibition (% I) at each inhibitor concentration (% I = 100 * (1- (I-C2) / (C1-C2)), where C1 is the average of the positive controls. Value, C2 is the average value of the negative control), and then% I = A + ((BA) / (1 + ((C / [I] ^ D))) (where , A is the lower asymptote, B is the upper asymptote, C is the IC ₅₀ value, and D is the slope factor), obtained by inserting% I vs inhibitor concentration [I] data was. When tested in this assay, the compound of example 6 to 28, IC ₅₀ was less than 100 micromolar.

  The present invention is illustrated by reference to the following examples, which should not be construed as limiting the invention.

General experimental details
LC / MS data was acquired under the following conditions:
・ Column: 3.3cm × 4.6mm ID, 3μm ABZ + PLUS
・ Flow rate: 3ml / min ・ Injection volume: 5μl
・ Temperature: Room temperature ・ UV detection range: 215 ~ 330nm
・ Solvent: A: 0.1% formic acid + 10 mM ammonium acetate
B: 95% acetonitrile + 0.05% Formic acid / Gradient: Time A% B%
0.00 100 0
0.70 100 0
4.20 0 100
5.30 0 100
5.50 100 0
¹ H NMR spectra were obtained at 400 MHz on a Bruker-Spectrospin Ultrashield 400 spectrophotometer.

Example 1

A solution of trifluoroacetic acid in dichloromethane (20%; 10 mL) of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid was converted to 5-biphenyl-4-yl-3-hydroxy-pentanoic acid tert-butyl ester (intermediate 3 244 mg, 0.748 mmol) and the resulting solution was stirred at room temperature for 45 minutes. Volatiles were evaporated under reduced pressure to give the title compound 5 (189 mg, 94%) as a white solid.

LC / MS: 3.24 min; z / e 271, calculated (M + 1) 271. ¹ H NMR (400 MHz: DMSO-d ₆ ): 7.65 (2 H), 7.55 (2 H), 7.43 (2 H), 7.31 (3 H), 4.79 (1 H), 3.85 (1 H), 2.70 (2 H), 2.35 (2 H), 1.71 (2 H).

Example 2

5- (9H-Fluoren-2-yl) -3-hydroxy-pentanoic acid Prepared as in Example 1. LC / MS: 3.22 min; z / e 281, calculated (M-1) 281.

Example 3

3-Hydroxy-5- (4-phenoxy-phenyl) -pentanoic acid Prepared as in Example 1. LC / MS: 3.11 min; z / e 285, calculated (M-1) 285.

Example 4

5- (4-Benzyloxy-phenyl) -3-hydroxy-pentanoic acid Prepared as in Example 1. LC / MS: 3.08 min; z / e 299, calculated (M-1) 299.

Example 5

5-Dibenzofuran-3-yl-3-hydroxy-pentanoic acid Prepared as in Example 1. LC / MS: 3.22 min; z / e 283, calculated (M-1) 283.

Example 6

5-biphenyl-4-yl-3-hydroxy-1-thiazolidin-3-yl- pentan -1- onediisopropylethylamine (32 μL, 0.19 mmol) was dissolved in dimethylformamide (1 mL) at room temperature under nitrogen. 5-biphenyl-4-yl-3-hydroxy-pentanoic acid (Example 1, 25 mg, 93 μmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyl To a stirred solution of uronium hexafluorophosphate (70 mg, 0.19 mmol). After stirring for 5 minutes, thiazolidine (11 μL, 0.14 mmol) was added and then stirring was continued for another 2 hours. Volatiles were removed by evaporation under reduced pressure and the residue was partitioned between dichloromethane (5 mL) and water (5 mL). These phases were separated and the organic phase was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (1: 1 ethyl acetate: 40-60 petroleum ether) to give the title compound (15 mg, 47%) as a white solid. LC / MS: 3.22 min; z / e 342, calculated (M + 1) 342. ¹ H NMR (400 MHz: CDCl ₃ ): 7.59 (2 H), 7.51 (2 H), 7.42 (2 H), 7.30 (3 H), 4.57, 4.42, 4.12, 3.85, 3.68, 3.09, 3.01, 2.90 2.76, 2.47 (2 H), 1.93 (1 H), 1.78 (1 H).

Example 7

5-biphenyl-4-yl-3-hydroxy-2-methylpentanoic acid A solution of trifluoroacetic acid in dichloromethane (20%; 10 mL) was added to tert-biphenyl-4-yl-2-methyl-3-oxo-pentanoic acid tert -Butyl ester (Intermediate 7, 130 mg, 0.382 mmol) was added and the resulting solution was stirred at room temperature for 1.5 hours. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (1: 2 ethyl acetate: 40-60 petroleum ether) to give the title compound as a white solid diastereoisomer mixture (60 mg, 56 %). LC / MS: 3.22 min; z / e 302, calculated (M + NH ₄ ) 302. ¹ H NMR (400 MHz: CDCl ₃ ): 7.59 (2 H), 7.51 (2 H), 7.40 (2 H), 7.28 (3 H), 4.21, 4.01 3.75, 2.91, 2.76, 2.62, 1.88, 1.25.

Example 8

2-Benzyl-5-biphenyl-4-yl-3-hydroxy-pentanoic acid Prepared analogously to Example 7 (diastereoisomer mixture). LC / MS: 3.54 and 3.61 min; z / e 378, calculated (M + NH ₄ ) 378.

Example 9

5-biphenyl-4-yl-3-hydroxy-2-phenethyl-pentanoic acid Prepared analogously to Example 7 (diastereoisomer mixture). LC / MS: 3.59 and 3.66 min; z / e 373, calculated (M-1) 373.

Example 10

5-Biphenyl-4-yl-3-hydroxy-2- (3-phenyl-propyl) -pentanoic acid Prepared similarly to Example 7 (diastereoisomer mixture). LC / MS: 3.71 and 3.79 min; z / e 387, calculated (M-1) 387.

Example 11
Biphenyl-4-yl-3-hydroxy-pentanoic acid-enantiomer 1
A racemic sample of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid (Example 1) was subjected to preparative chiral HPLC (Chiralpak-AD column, 15% ethanol: heptane (0.1% trifluoroacetic acid) for 13.5 minutes. 15 mL / min).

Example 12
Biphenyl-4-yl-3-hydroxy-pentanoic acid-enantiomer 2
A racemic sample of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid (Example 1) was subjected to preparative chiral HPLC (Chiralpak-AD column, 15% ethanol: heptane (0.1% trifluoroacetic acid) for 15.2 minutes. 15 mL / min).

Example 13

3-Hydroxy-5- (3'-nitro-biphenyl-4-yl) -pentanoic acid
3-Hydroxy-5- (4-iodo-phenyl) -pentanoic acid (intermediate 10, 16 mg, 50 μmol), cesium carbonate (40 mg, 125 μmol), 3-nitrophenylboronic acid (10 mg, 60 μmol) and FiberCat ™ 1001 (20 mg, 2.7% w / w palladium) was suspended in dimethylformamide (200 μL) and then heated at 100 ° C. for 1 hour. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between 10% methanol / dichloromethane and 2M HCl, then the phases were separated. The organic phase was evaporated under reduced pressure and purified by mass directed HPLC to give the title compound (5 mg, 32%) as a white solid. LC / MS: 3.18 min; z / e 314, calculated (M-1) 314. ¹ H NMR (400 MHz: DMSO-d ₆ ): 8.4 (1 H), 8.15 (2 H), 7.7 (3 H), 7.35 (2 H), 3.85 (1 H), 2.7 (2 H), 2.32 (2 H), 1.7 (2 H).

Example 14

3-hydroxy-5- (4′-methyl-biphenyl-4-yl) -pentanoic acid Prepared as in Example 13. LC / MS: 3.43 min; z / e 283, calculated (M-1) 283.

Example 15

3-hydroxy-5- (4′-hydroxymethyl-biphenyl-4-yl) -pentanoic acid Prepared as in Example 13. LC / MS: 2.71 min; z / e 299, calculated (M-1) 299.

Example 16

3-hydroxy-5- (3′-methyl-biphenyl-4-yl) -pentanoic acid Prepared as in Example 13. LC / MS: 3.36 min; z / e 283, calculated (M-1) 283.

Example 17

3-hydroxy-5- (3′-hydroxy-biphenyl-4-yl) -pentanoic acid Prepared as in Example 13. LC / MS: 2.86 min; z / e 285, calculated (M-1) 285.

Example 18

5- (4′-acetyl-biphenyl-4-yl) -3-hydroxy-pentanoic acid Prepared as in Example 13. LC / MS: 3.02 min; z / e 311, calculated (M-1) 311.

Example 19

5- (3′-Acetylamino-biphenyl-4-yl) -3-hydroxy-pentanoic acid Prepared as in Example 13. LC / MS: 2.71 min; z / e 326, calculated (M-1) 326.

Example 20

5- (3′-Fluoro-biphenyl-4-yl) -3-hydroxy-pentanoic acid Prepared as in Example 13. LC / MS: 3.27 min; z / e 287, calculated (M-1) 287.

Example 21

3-Hydroxy-5- (4′-methylsulfanyl-biphenyl-4-yl) -pentanoic acid Prepared as in Example 13. LC / MS: 3.44 min; z / e 315, calculated (M-1) 315.

Example 22

5- (4′-Ethyl-biphenyl-4-yl) -3-hydroxy-pentanoic acid Prepared as in Example 13. LC / MS: 3.60 min; z / e 297, calculated (M-1) 297.

Example 23

5- (4′-Ethoxy-biphenyl-4-yl) -3-hydroxy-pentanoic acid Prepared as in Example 13. LC / MS: 3.40 min; z / e 313, calculated (M-1) 313.

Example 24

5- (4′-Cyano-biphenyl-4-yl) -3-hydroxy-pentanoic acid Prepared as in Example 13. LC / MS: 3.08 min; z / e 294, calculated (M-1) 294.

Example 25

5- (3'-Cyano-biphenyl-4-yl) -3-hydroxy-pentanoic acid Prepared as in Example 13. LC / MS: 3.05 min; z / e 294, calculated (M-1) 294.

Example 26

5- (4′-Fluoro-biphenyl-4-yl) -3-hydroxy-pentanoic acid Prepared as in Example 13. LC / MS: 3.26 min; z / e 287, calculated (M-1) 287.

Example 27

3-Hydroxy-5- (4′-phenoxy-biphenyl-4-yl) -pentanoic acid Prepared as in Example 13. LC / MS: 3.73 min; z / e 361, calculated (M-1) 361.

Example 28

3-hydroxy-5- (4′-methoxy-biphenyl-4-yl) -pentanoic acid Prepared as in Example 13. LC / MS: 3.19 min; z / e 299, calculated (M-1) 299.

Intermediate 1

4- Bromomethylbiphenyl carbon tetrabromide (8.99 g, 27.1 mmol) and triphenylphosphine (7.11 g, 27.1 mmol) were dissolved in dichloromethane (100 mL) at room temperature in biphenyl-4-ylmethanol (5.00 g, 27.1 mmol) was added to the stirred solution. Stirring was continued at room temperature for 1.5 hours and then the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel (1:20 diethyl ether: cyclohexane) to give the title compound (6.37 g, 95%) as a white solid. ¹ H NMR (400 MHz: CDCl ₃ ): 7.6 (4 H), 7.45 (4 H), 7.35 (1 H), 4.55 (2 H).

Intermediate 2

A solution of t-butyl acetoacetate (1.84 mL, 11.1 mmol) in 5-biphenyl-4-yl-3-oxo-pentanoic acid tert-butyl ester tetrahydrofuran (20 mL) was added tetrahydrofuran (10 mL) at 0 ° C. under nitrogen. To a stirred suspension of sodium hydride dissolved in (488 mg, 12.2 mmol). After stirring for 10 minutes, n-butyllithium (1.6M in hexane; 7.3 mL, 11.6 mmol) was added dropwise over 2 minutes, then stirring was continued for another 10 minutes. A solution of 4-bromomethyl-biphenyl (Intermediate 1, 3.00 g, 12.2 mmol) in tetrahydrofuran (6 mL) was added dropwise over 10 minutes and the resulting solution was stirred at 0 ° C. for 1.5 hours. 6M hydrochloric acid (15 mL) was added and then the crude reaction mixture was extracted with diethyl ether (3 × 50 mL). After the organic phases were combined, washed with brine (50 mL) and dried (MgSO ₄ ), the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (1:20 diethyl ether: cyclohexane) to give the title compound (1.37 g, 38%) as a yellow solid. LC / MS: 3.78 min; z / e 342, calculated (M + NH ₄ ) 342. ¹ H NMR (400 MHz: CDCl ₃ ): 7.55 (2 H), 7.50 (2 H), 7.43 (2 H), 7.32 (1 H), 7.25 (2 H), 3.34 (2 H), 2.95 (4 H), 1.45 (9 H).

Intermediate 3

5-biphenyl-4-yl-3-hydroxy-pentanoic acid tert-butyl ester sodium borohydride (51 mg, 1.4 mmol) was added 5-biphenyl-4-yl in methanol (5 mL) at 0 ° C. under nitrogen. To a stirred solution of -3-oxo-pentanoic acid tert-butyl ester (Intermediate 2, 400 mg, 1.23 mmol) was added in one portion. Stirring was continued for 30 minutes, then 1M hydrochloric acid (5 mL) was added. The crude reaction mixture was extracted with diethyl ether (3 × 20 mL), the resulting organic phases were combined, dried (MgSO ₄ ), and then the solvent was removed by evaporation under reduced pressure to give the title compound as a colorless oil ( 375 mg, 93%). LC / MS: 3.67 min; z / e 344, calculated (M + NH ₄ ) 344. ¹ H NMR (400 MHz: CDCl ₃ ): 7.55 (2 H), 7.50 (2 H), 7.43 (2 H), 7.38 (3 H), 4.01 (1 H), 3.25 (1 H), 2.80 (2 H), 2.44 (2 H), 1.82 (2 H), 1.45 (9 H).

Intermediate 4

5-biphenyl-4-yl-3-methoxy-pentanoic acid tert-butyl ester sodium hydride (60%; 7.0 mg, 0.17 mmol) was added 5% in dimethylformamide (0.5 mL) at 0 ° C. under nitrogen. -Biphenyl-4-yl-3-hydroxy-pentanoic acid tert-butyl ester (Intermediate 3, 50 mg, 0.15 mmol) was added to the stirred solution. After stirring for 5 minutes, methyl iodide (14 μL, 0.23 mmol) was added and stirring was continued for 12 hours. Volatiles were evaporated under reduced pressure and the residue was partitioned between dichloromethane (5 mL) and water (5 mL). The phases were separated, the organic phase was dried (MgSO ₄ ) and then the solvent was evaporated. The residue was purified by column chromatography on silica gel (1: 8 diethyl ether: cyclohexane) to give the title compound (18 mg, 35%) as a colorless gum. LC / MS: 3.87 min; z / e 358, calculated (M + NH ₄ ) 358. ¹ H NMR (400 MHz: CDCl ₃ ): 7.59 (2 H), 7.53 (2 H), 7.42 (2 H), 7.28 (3 H), 3.68 (1 H), 3.40 (3 H), 2.77 (2 H), 2.56 (1 H), 2.38 (1 H), 1.88 (2 H), 1.47 (9 H).

Intermediate 5

3-Acetoxy-5-biphenyl-4-yl-pentanoic acid tert-butyl ester acetic anhydride (40 μL, 0.42 mmol) was added 5-biphenyl-4-yl-3 in dichloromethane (1 mL) at room temperature under nitrogen. -Hydroxy-pentanoic acid tert-butyl ester (Intermediate 3, 54 mg, 0.17 mmol), 4-dimethylaminopyridine (5.0 mg, 41 μmol) and pyridine (54 μL, 0.66 mol) were added to a stirred solution. After stirring at room temperature for 12 hours, 2M hydrochloric acid (5 mL) and dichloromethane (5 mL) were added. These phases were separated and the aqueous phase was extracted with dichloromethane (3 × 5 mL). The organic phases were combined, washed with brine (5 mL) and dried (MgSO ₄ ). The solvent was removed by evaporation under reduced pressure to give the title compound (45 mg, 74%) as a colorless gum. LC / MS: 3.91 min; z / e 386, calculated (M + NH ₄ ) 386. ¹ H NMR (400 MHz: CDCl ₃ ): 7.59 (2 H), 7.52 (2 H), 7.42 (2 H), 7.33 (1 H), 7.25 (2 H), 5.29 (1 H), 2.70 (2 H), 2.53 (2 H), 2.05 (3 H), 1.97 (2H), 1.42 (9 H).

Intermediate 6

5-biphenyl-4-yl-2-oxo-3-pentanoic acid tert-butyl ester 5-biphenyl-4-yl-3-oxo-pentanoic acid tert-butyl ester in dimethylformamide (1.5 mL) Body 2, 0.30 g, 0.93 mmol) solution was added to a suspension of sodium hydride (60%; 38 mg, 0.94 mmol) in dimethylformamide (1 mL) at 0 ° C. under nitrogen. After stirring for 20 minutes, methyl iodide (58 μL, 0.93 mmol) was added and the reaction was allowed to warm to room temperature and stirring was continued at that temperature for 2 hours. 0.5M hydrochloric acid (5 mL) was added and the quenched reaction mixture was extracted with diethyl ether (3 × 5 mL). The organic phases were combined, washed with brine (5 mL) and dried (MgSO ₄ ). Volatiles were removed by evaporation under reduced pressure and the residue was purified by column chromatography on silica gel (1: 6 diethyl ether: 40-60 petroleum ether) to give the title compound (163 mg, 52%) as a colorless oil. It was. LC / MS: 3.81 min; z / e 356, calculated (M + NH ₄ ) 356. ¹ H NMR (400 MHz: CDCl ₃ ): 7.59 (2 H), 7.51 (2 H), 7.42 (2 H), 7.32 (1 H), 7.22 (2 H), 3.42 (1 H), 2.97 (3 H), 2.83 (1 H), 1.42 (9 H), 1.28 (3 H).

Intermediate 7

5-biphenyl-4-yl-3-hydroxy-2-methyl-pentanoic acid tert-butyl ester sodium borohydride (17 mg, 0.44 mmol) was added in methanol (3 mL) at 0 ° C. under nitrogen. To a stirred solution of biphenyl-4-yl-2-methyl-3-oxo-pentanoic acid tert-butyl ester (Intermediate 6, 135 mg, 0.399 mmol). After stirring for 1 hour, 1M hydrochloric acid (5 mL) was added and the crude reaction mixture was extracted with diethyl ether (3 × 5 mL). The organic phases were combined, washed with brine (5 mL) and dried (MgSO ₄ ). Volatiles were removed by evaporation under reduced pressure to give the title compound (130 mg, 96%) as a colorless gum of a mixture of diastereoisomers. LC / MS: 3.72 min; z / e 341, calculated (M + 1) 341. ¹ H NMR (400 MHz: CDCl ₃ ): 7.59 (2 H), 7.51 (2 H), 7.42 (2 H), 7.28 (3 H), 4.21, 3.90, 3.65, 2.89, 2.75, 1.81, 1.69, 1.55 , 1.44, 1.30, 1.18.

Intermediate 8

5- (4-Iodo-phenyl) -3-oxo-pentanoic acid tert-butyl ester
Butyl acetoacetate (1.5 mL, 9.2 mmol) was added dropwise over 2 minutes to a stirred suspension of sodium hydride (60%; 400 mg, 10.0 mmol) in tetrahydrofuran at 0 ° C. under nitrogen. added. After stirring for 10 minutes, n-butyllithium (1.6M; 6.0 mL, 9.6 mmol) dissolved in hexane was added and stirring was continued for 10 minutes. The resulting solution was treated dropwise with a solution of 4-iodobenzyl bromide (2.97 g, 10.0 mmol) in tetrahydrofuran (4 mL) and then allowed to warm to room temperature. The reaction was stirred at room temperature for 40 minutes and then quenched with 6M HCl (5 mL). The resulting mixture was extracted with diethyl ether (3 × 50 mL). The organic phases were combined, washed with brine (50 mL), dried (MgSO ₄ ) and then the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:20 to 1:10 ethyl acetate / cyclohexane) to give the title compound (1.88 g, 54%) as a yellow oil. LC / MS: 3.66 min; z / e 375, calculated (M + 1) 375. ¹ H NMR (400 MHz; CDCl ₃ ): 7.6 (2 H), 6.93 (2 H), 3.33 (2 H), 2.85 (4 H), 1.45 (9 H).

Intermediate 9

3-hydroxy-5- (4-iodo-phenyl) -pentanoic acid tert-butyl ester sodium borohydride (198 mg, 5.20 mmol) was added at 0 ° C. in 5- (4-iodo- Phenyl) -3-oxo-pentanoic acid tert-butyl ester (Intermediate 8, 1.78 g, 4.76 mmol) was added in one portion. The reaction was stirred for 20 minutes and then quenched with 1M HCl (15 mL). The resulting mixture was extracted with diethyl ether (3 × 20 mL). The organic phases were combined and dried (MgSO ₄ ), then the solvent was removed by evaporation under reduced pressure to give the title compound (1.46 g, 82%) as a colorless oil. LC / MS: 3.59 min; z / e 394, calculated (M + NH ₄ ) 394. ¹ H NMR (400 MHz: CDCl ₃ ): 7.6 (2 H), 6.95 (2 H), 3.95 (1 H), 2.7 (2 H), 2.38 (2 H), 1.73 (2 H), 1.45 (9 H).

Intermediate 10

3-hydroxy-5- (4-iodo-phenyl) -pentanoic acid silica gel (19 g) was dissolved in toluene (100 mL) and 3-hydroxy-5- (4-iodo-phenyl) -pentanoic acid tert-butyl ester ( Intermediate 9 (1.2 g, 3.2 mmol) was added to a stirred solution and the resulting suspension was heated to reflux for 5.5 hours. The reaction was cooled to room temperature then filtered through a thin pad of celite and washed with 20% methanol / dichloromethane (2 × 50 mL). The filtrate was evaporated under reduced pressure to give the title compound (586 mg, 57%) as a white solid. LC / MS: 3.01 min; z / e 319, calculated (M-1) 319. ¹ H NMR (400 MHz: DMSO-d ₆ ): 7.63 (2 H), 7.00 (2 H), 3.77 (1 H), 2.60 (2 H), 2.3 (2 H), 1.62 (2 H).

Claims (7)

Formula (I):

(Where
Q represents an optionally substituted 5- or 6-membered aryl or heteroaryl ring;
X represents O, S, NR ⁵ , or CR ⁶ R ⁷ ;
Y represents CHOH, CHSH, NOR ⁸ , CNR ⁸ , or CNOR ⁸ ;
Z represents a bond, CR ¹⁰ R ¹¹ , O, S, SO, SO ₂ , NR ¹⁰ , OCR ¹⁰ R ¹¹ , CR ¹⁰ R ¹¹ O, or Z, R ⁴ and Q are taken together Forming an optionally substituted fused tricyclic group;
R ¹ , R ¹ ′, R ³ and R ³ ′ independently of one another represent H, C _1-6 alkyl, or C _1-4 alkylaryl;
R ² represents CO ₂ R ⁸ , CONR ⁵ OR ⁹ , or NR ⁵ COR ⁹ ;
R ⁴ represents optionally substituted 5 or 6 membered aryl or heteroaryl;
R ⁵ represents H or C _1-3 alkyl;
R ⁶ and R ⁷ independently of one another represent H, C _1-3 alkyl, or halogen;
R ⁸ represents H or C _1-2 alkyl;
R ⁹ represents H or C _1-3 alkyl;
R ¹⁰ and R ¹¹ independently of one another represent H, C _1-6 alkyl, or C _1-4 alkylaryl)
And the physiologically functional derivatives thereof (excluding 6H-dibenzo [b, d] pyran-3-pentanoic acid (1-dihydroxy-6,6,9-trimethyl) except that As a condition:
Q represents phenyl; X is O, S or CR ⁶ R ⁷ , wherein R ⁶ and R ⁷ independently of one another represent H or C _1-3 alkyl; Z is a bond, C _{2-4 represents} alkylene, S, SO, SO ₂ , OCH ₂ , or CH ₂ O; when Y represents CHOH, R ⁴ represents a substituent X′W ′ (wherein X ′ represents —NR ¹ C (O) NR ^2- , -NR ¹ C (O)-, -NR ¹ C (O) O-, -C (O) NR ^2- , or -OC (O) NR ^2- (where R ¹ and R ² are independently selected from hydrogen, C _1-4 alkyl and C _1-4 haloalkyl) and W ′ is hydrogen, or hydrogen, C _1-4 alkyl, C _{1- A} C _1-12 hydrocarbyl group optionally substituted by one or more groups independently selected from ₄ alkoxy, hydroxy, C _1-4 haloalkyl, and C _1-4 haloalkoxy) Not phenyl substituted at the ortho position by; and
R ⁴ , Z and Q together are a group:

(Where
R ¹ ′ is H, C _1-6 alkyl, C _1-4 alkoxy C _1-4 alkyl, C _1-6 alkanoyl, C _1-4 alkanoyl C _1-4 alkyl, aryl, aryl C _1-4 alkyl, Aryl-C _1-4 alkoxy C _1-4 alkyl, aryl C _1-4 alkanoyl, arylcarbonyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _1-4 alkoxy C _1-4 alkyl, heteroaryl C _1-4 alkanoyl, heteroarylcarbonyl, heterocyclyl, heterocyclyl C _1-4 alkyl, heterocyclyl C _1-4 alkoxy C _1-4 alkyl, heterocyclyl C _1-4 alkanoyl, heterocyclylcarbonyl, carbocyclyl, carbocyclyl C _1-4 alkyl, carbocyclyl C _1-4 alkoxy C _1-4 alkyl, carbocyclyl C _1-4 alkanoyl, carbocyclylalkyl carbonyl, C _1-4 alkylsulfonyl, N, N-di -C _1-4 A A kill aminosulfonyl or NC _1-4 alkylaminosulfonyl, wherein, R ¹ 'is (optionally substituted by 3 or fewer fluro (Fluro) substituents) C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkanoyl, carboxy, hydroxy, halogen, cyano, amino, NC _1-4 alkylamino, N, N-di-C _1-4 alkylamino, C _1-4 alkanoylamino, mercapto , C _1-4 alkylsulfonyl, C _1-4 alkylsulfinyl, C _1-4 alkylsulfanyl, nitro, heteroaryl C _1-4 alkanoylamino, or C _1-4 3 or less independently selected from alkoxycarbonyl Optionally substituted by a substituent of
R ² ′ is hydrogen, C _1-4 alkyl (optionally substituted by hydroxy), C _1-4 alkoxy, cyano, nitro, halogen, amino, NC _1-4 alkylamino, or N, N Selected from -dialkylamino;
R ⁴ ′ is selected from hydrogen, C _1-4 alkyl, halogen, or nitro)
If you form
X is NH or CR ⁶ R ⁷ ;
Y is CHOH;
R ² is not CO ₂ R ⁸ (wherein R ⁸ is C _1-2 alkyl). Formula (Ia):

(Where:
T is absent or represents O, S, NR ¹⁷ or CR ¹⁷ R ¹⁸ ;
--- optionally represents a bond;
R ¹⁵ and R ¹⁶ are independently of each other halogen, cyano, nitro, OR ¹⁷ , SR ¹⁷ , COR ¹⁷ , NR ¹⁸ COR ¹⁷ , CONR ¹⁷ R ¹⁸ , optionally substituted phenoxy, or OR ¹⁷ Represents optionally substituted C _1-6 alkyl;
R ¹⁷ represents H, C _1-6 alkyl or C _1-4 alkylaryl;
R ¹⁸ represents H or C _1-6 alkyl;
m and n independently of one another represent 0 or an integer of 1, 2 or 3;
(However, if T is not present, R ¹⁵ is not ortho-position NR ¹⁸ COR ¹⁷ or CONR ¹⁷ R ¹⁸ )
The compound according to claim 1 represented by the formula: and a physiologically functional derivative thereof.   3. A compound according to claim 1 or claim 2 for use in medicine.   A method of treating a human or animal subject suffering from or susceptible to an autoimmune disease or inflammatory condition, the compound of claim 1 or claim 2 in an effective amount to the human or animal subject. Said method comprising administering.   Use of a compound according to claim 1 or claim 2 in the manufacture of a medicament for the treatment of inflammatory conditions or autoimmune diseases.   A pharmaceutical composition comprising a compound according to claim 1 or claim 2 and a pharmaceutically acceptable carrier thereof, and optionally one or more other therapeutic agents. A process for the preparation of a compound of formula (I) as defined in claim 1, comprising
(A) Formula (II):

(Wherein R ¹ , R ¹ ′, R ² , R ³ , R ³ ′, Q, X and Y are as previously defined for formula (I) and L represents a leaving group)
Reacting a compound represented by: with a reagent suitable for introducing the group R ⁴ Z; or
(B) Formula (III):

(Wherein R ⁴ , Z, Q, X, R ¹ , R ¹ ′, R ³ , R ³ ′ and R ² are as previously defined for formula (I))
Oxidizing the compound represented by: or
(C) In the presence of a base, the formula (IV):

Wherein R ⁴ , Z and Q are as previously defined for formula (I) and X represents O or S
A compound represented by the formula (VA) or (VB):

(Wherein R ¹ , R ¹ ′, R ³ , R ³ ′ and R ² are as previously defined for formula (I) and L is a leaving group)
Reacting with a compound represented by: or
(D) interconverting one compound of formula (I) with another compound of formula (I); or
(E) deprotecting a protected derivative of the compound represented by formula (I);
Including said method.